Abstract
An Australian marine tunicate-derived fungus, Talaromyces sp. CMB-TU011 was subjected to a program of analytical microbioreactor (MATRIX) cultivations, supported by UHPLC-QTOF profiling, to reveal conditions for producing a new class of extensively N-methylated 11-12 residue linear peptides, talaropeptides A-D (2-5). The structures for 2-5, inclusive of absolute configurations, were determined by a combination of detailed spectroscopic and chemical (e.g., C3 and C18 Marfey's) analyses. We report on the biological properties of 2-5, including plasma stability, as well as antibacterial, antifungal and cell cytotoxicity. The talaropeptide mega non-ribosomal peptide synthetase (NRPS) is described, as second only in size to that for the fungus-derived immunosuppressant cyclosporine (an 11-residue extensively N-methylated cyclic peptide).
Highlights
We described the structure elucidation of a first-in-class cyclic hexapeptide containing a rare hydroxamate residue, talarolide A (1) (Figure 1), isolated from an Australian marine tunicate-derived fungus, Talaromyces sp
ultra-high-performance liquid chromatography (UHPLC)-quadrupole time of flight (QTOF) analysis of MATRIX cultivations revealed that YES static broth cultivation was optimum for the production of talaropeptides (Figures S2–S4)
With analytical high-performance liquid chromatography (HPLC)-diode array detector (DAD)-ESIMS localizing 2-5 in the MeOH solubles, this material was subjected to gel chromatography (Sephadex LH-20, MeOH) followed by semi-preparative reversed phase HPLC chromatography, to yield talaropeptides A (2, 1.3 mg), B (3, 1.3 mg), C (4, 1.8 mg), and D (5, 2.8 mg) (Figure 1)
Summary
We described the structure elucidation of a first-in-class cyclic hexapeptide containing a rare hydroxamate residue, talarolide A (1) (Figure 1), isolated from an Australian marine tunicate-derived fungus, Talaromyces sp. In an effort to optimize the production of 1, we report on a 24-well microbioreactor cultivation analysis (known in-lab as the MATRIX), using a combination of 11 different media and 3 phases (i.e., solid agar, as well as static and shaken broth). While this study successfully revealed optimal conditions for the production of 1, including new analogs (work-in-progress), it revealed conditions where talarolide production was fully suppressed in favor of a new class of extensively N-methylated linear peptides. This report provides an account of the production, isolation and characterisation of these new peptides, talaropeptides A-D (2-5), where structure elucidation inclusive of absolute configurations was achieved by a combination of detailed spectroscopic and chemical analyses. We take the opportunity to report on the biological properties of 2-5, and document the mega non-ribosomal peptide synthetase (NRPS) responsible for the biosynthesis of talaropeptides
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